Martin Turner - Head of Laboratory
B Cell signalling and development
The molecular processes which control the development and function of lymphocytes have been extensively studied from the perspective of cell surface receptors and their associated intracellular signalling. Also, many transcription factors which repress or promote the production of mRNA have been identified as being essential for lymphocyte development and activation. These studies have revealed that genes, molecules and pathways that are used early in the development of lymphocytes are re-used in fully mature cells as part of the response to infection. Examples of this include signalling pathways such as the PI3K and ERK pathways and transcription factors such as the E2A, BCL-6, STATs, GATA-3 or Notch-1; all are required for lymphocyte development, but also for the proper responses of mature lymphocytes. This important principle has been revealed using mouse models in which genes are deleted at specific developmental stages.
Changes in gene transcription alone do not account for many dynamic changes in gene expression. However, the contribution of post-transcriptional regulation is still unclear. The discovery of microRNA-mediated control has led to an explosion of research into this fundamental mechanism regulating gene expression. However there are approximately 700 RNA-binding proteins (RBP) encoded within the genome and for most, their functions in splicing, polyadenylation, mRNA transport and localisation, as well as mRNA stability and translational efficiency remain to be defined. Furthermore, appreciation of the regulation of RBP function via phosphorylation, ubiquitination etc will be crucial for a complete understanding of signal transduction.
At Babraham, we aim to characterise fundamental mechanisms controlling lymphocyte development and function. In the future explaining how these are integrated will be an important step towards a systems level understanding of immunity. Genetically modified mice in which the functions of signalling pathways and RNA–binding proteins can be controlled by conditional mutagenesis are one important research tool required for this understanding. Additionally, we are developing tools for measuring gene expression in rare cell populations. We also use genome wide approaches to study RNA turnover and translation and to identify the targets of RBP. Our approach trains individuals who can combine molecular, cellular and in vivo skills to tackle biological questions.
Figure 1
Circulating lymphoblasts in a peripheral blood smear from a mouse lacking both TIS11b and TIS11d in T cells. TIS11b and TIS11d are RNA-binding proteins which regulate mRNA degradation and translational repression.
Photo courtesy of Dan Hodson.
Mice lacking TIS11b and TIS11d after Cre-mediated recombination during T cell development develop a Notch1 dependent T cell acute lymphoblastic leukaemia (T-ALL). Both TIS11b and TIS11d interact with AU-rich sequences within the 3’ untranslated region of Notch1 mRNA and suppress Notch1 expression. TIS11b and TIS11d are thus redundant tumour suppressors which also play a role in T cell development. Further studies are underway to understand the function of these genes in other lymphocytes subsets.
Figure 2
Tis11b has been shown to be a component of processing bodies, RNA protein complexes which mediate RNA decay. This image shows localisation of TIS11b with the decapping enzyme Dcp-1 in activated lymphocytes. The function of processing bodies in lymphocytes is unknown and is under investigation in the laboratory.
Photo courtesy of Manuel Diaz-Munoz.
Recent, selected publications
(further publications are listed here)
Hodson DJ, Janas ML, Galloway A, Bell SE, Andrews SA, Li CM, Pannell R, Siebel CW, MacDonald HR, De Keersmaecker K, Ferrando AA, Grutz G, Turner M (In press) Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T-lymphoblastic leukaemia.
Nature Immunology (in press)
Rolf J, Fairfax K, Turner M (2010) Signaling pathways in T follicular helper cells.
Journal of Immunology 184 6563-6568
http://dx.doi.org/10.4049/jimmunol.1000202
Gururajan M, Haga CL, Das S, Leu C-M, Hodson DJ, Josson S, Turner M, Cooper MD (2010) MicroRNA 125b inhibition of B cell differentiation in germinal centers.
International Immunology 22 583-592
http://dx.doi.org/10.1093/intimm/dxq042
Kovesdi D, Bell SE, Turner M (In press) The development of mature B lymphocytes requires the combined function of CD19 and the p110δ subunit of PI3K.
Self/Nonself (in press)
Janas M, Varano G, Gudmundsson K, Noda M, Nagasawa T, Turner M (2010) Thymic development beyond β-selection requires phosphatidylinositol 3-kinase activation by CXCR4.
Journal of Experimental Medicine 207 247-261
http://dx.doi.org/10.1084/jem.20091430
Henley TW, Kovesdi D, Turner M (2008) B-cell responses to B-cell activation factor of the TNF family (BAFF) are impaired in the absence of PI3K delta.
European Journal of Immunology 38 3543-3548
http://dx.doi.org/10.1002/eji.200838618
Janas ML, Hodson D, Stamataki Z, Hill S, Welch K, Gambardella L, Trotman LC, Pandolfi PP, Vigorito E, Turner M (2008) The effect of deleting p110δ on the phenotype and function of PTEN-deficient B cells.
Journal of Immunology 180 739-746
http://www.jimmunol.org/cgi/content/full/180/2/739
Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, Kohlhaas S, Das PP, Miska EA, Rodriguez A, Bradley A, Smith KGC, Rada C, Enright AJ, Toellner K-M, MacLennan ICM, Turner M (2007) microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells.
Immunity 27 847-859
http://dx.doi.org/10.1016/j.immuni.2007.10.009
Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DA, Van Dongen S, Grocock RJ, Das PP, Miska EA, Vetrie D, Okkenhaug K, Enright AJ, Dougan G, Turner M, Bradley A (2007) Requirement of bic/microRNA-155 for normal immune function.
Science 316 608-611
http://dx.doi.org/10.1126/science.1139253
Bell SE, Sanchez MJ, Spasic-Boskovic O, Santalucia T, Gambardella L, Burton GJ, Murphy JJ, Norton JD, Clark AR, Turner M (2006) The RNA binding protein Zfp36l1 is required for normal vascularisation and post-transcriptionally regulates VEGF expression.
Developmental Dynamics 235 3144-3155
http://dx.doi.org/10.1002/dvdy.20949
Martin Turner - Head of Laboratory
Kirsty Bates - Research Assistant
Sarah Bell - Senior Research Associate
Nerys Evans - Research Assistant
Alison Galloway - PhD student
Michelle Janas - Senior Postdoctoral Scientist
Sebastian Lukasiak - Postdoctoral Scientist
Manuel Diaz-Munoz - Postdoctoral Scientist
Julia Rolf - Postdoctoral Scientist
Page updated 20 July, 2010
